Dose rationale for gabapentin and tramadol in pediatric patients with chronic pain

Abstract Despite off‐label use, the efficacy and safety of gabapentin and tramadol in pediatric patients (3 months to <18 years old) diagnosed with chronic pain has not been characterized. However, generating evidence based on randomized clinical trials in this population has been extremely challenging. The current investigation illustrates the use of clinical trial simulations (CTSs) as a tool for optimizing doses and protocol design for a prospective investigation in pediatric patients with chronic pain. Pharmacokinetic (PK) modeling and CTSs were used to describe the PKs of gabapentin and tramadol in the target population. In the absence of biomarkers of analgesia, systemic exposure (AUC, Css) was used to guide dose selection under the assumption of a comparable exposure‐response (PKPD) relationship for either compound between adults and children. Two weight bands were identified for gabapentin, with doses titrated from 5 to 63 mg/kg. This yields gabapentin exposures (AUC0–8) of approximately 35 mg/L*h (1200 mg/day adult dose equivalent). For tramadol, median steady state concentrations between 200 and 300 ng/mL were achieved after doses of 2–5 mg/kg, but concentrations showed high interindividual variability. Simulation scenarios showed that titration steps are required to explore therapeutically relevant dose ranges taking into account the safety profile of both drugs. Gabapentin can be used t.i.d. at doses between 7–63 and 5–45 mg/kg for patients receiving gabapentin weighing <15 and ≥15 kg, respectively, whereas a t.i.d. regimen with doses between 1 and 5 mg/kg can be used for tramadol in patients who are not fast metabolisers.


Gabapentin Target Exposure
In the absence of biomarkers and evidence indicating that the mechanisms underpinning the antihyperalgesic effects of gabapentin would be age-dependent, doses used in the simulations and, ultimately in the proposed dosing regimen for pediatric patients, were based on the assumption that comparable exposure would result in similar pharmacological activity and potentially comparable clinical response.We have therefore referred to the available exposure-response curve in adult neuropathic pain patients, and identified the target exposure range that is associated with clinical efficacy.
Based on the Neurontin® NDA submission file [1] (Figure S1), it was possible to extract secondary PK parameters associated with each dose level in the dose ranging study performed in adult neuropathic pain patients.As shown in Table S1, exposure ranges associated with clinical efficacy in adults were used as target for pediatric patients.Gabapentin exposure-response relationship derived from dose ranging studies in adult neuropathic pain patients using the Likert pain scale (Neurontin®, NDA submission file [1] ).
Table S1.Secondary PK parameters describing the systemic exposure to gabapentin after increasing doses of gabapentin.The data are presented as mean values.Cmax = maximum steady-state plasma concentration; AUC 0-8 = area under the steady-state plasma concentration-time curve from 0 time until 8 h after administration; Ae% = percentage of dose eliminated as unchanged drug in urine.

Gabapentin Population Pharmacokinetic Model
We selected the model reported by Ouellet et al. [2] for subsequent extrapolation of the pharmacokinetics of gabapentin in children and implementation of simulation scenarios in children with chronic neuropathic pain.
The basic structural model, shown in Figure S2, is a one-compartment model with estimates of oral clearance (CL/F), central volume of distribution (Vd/F), first-order rate of absorption constant (ka), and lag-time prior to absorption (Tlag).Inter-subject variability of all PK parameters was described using an exponential model.It should be noted that as the bioavailability of gabapentin is not dose proportional, changes in exposure due to variable F were described according to the following equation: where F is the relative bioavailability of gabapentin.We have assumed that the dose-dependent decrease in bioavailability also applies to the paediatric population, irrespective of the use of a liquid dosage form.

Tramadol Target Exposure
Tramadol is commonly prescribed for acute pain in paediatric patients, but it is not recommended for children below 12 years of age [3] .While the analgesic effects of tramadol at the currently approved doses has been shown to be dose dependent and associated with serum concentrations of 0.1-0.3mg/L, there are no published data in chronic or neuropathic pain patients, in which pharmacokinetic data have been collected.
Therefore, our working hypothesis is that nociception in chronic pain is determined by the same mechanisms underlying opioid activity in acute pain, irrespective of age.Differences in pharmacodynamic effects are more likely to occur due to phenomena such as tolerance.
Bearing in mind the large interindividual variability in the metabolism of tramadol, a dose rationale was proposed for paediatric patients with chronic pain, which allows up-titration to mean peak concentrations that correspond to the recommended titration regimen in adults, namely a maximum of 400 mg/day.This regimen ensures mean peak plasma concentrations of tramadol remain below 0.75 mg/L, a level which has not been associated with respiratory depression or other relevant adverse events.

Tramadol Population Pharmacokinetic Model
The population pharmacokinetic model published by Garrido et al. [4] was adapted for the purposes of our simulation work (Table S3).The disposition of tramadol in plasma was best characterized by a two- Information on the absorption rate constant was incorporated into the model using the data from Payne et al. [5] , whose study population was administered tramadol oral drops (chosen formulation for the GABA-1 study protocol).

Demographic Characteristics -Virtual Population
A virtual cohort of patients was created for the purpose of this analysis using demographic and clinical baseline characteristics from three databases, namely, National Health and Nutrition Examination Survey of CDC (NHANES) [6] , CALIPER [7] and the WHO [8] .Patient data between 3 months and 5 years were obtained from the WHO Child growth standards, whilst data for those aged between 2 years and 18 years old were retrieved from NHANES.Serum creatinine, which was required to calculate creatine clearance, was extracted from the CALIPER database.
Individual baseline characteristics were selected based on previously defined covariate factors known to affect the disposition of gabapentin and tramadol, namely: body weight, sex, height, age and serum creatinine.Creatinine clearance was required for the characterization of gabapentin disposition.It was calculated from serum creatinine values, stratified by age and sex; the Schwartz formula [9] was used for patients aged 3 months to 12 years and the Cockcroft-Gault [10] formula for individuals aged 12 years and above.
Table S3.Parameter estimates of final pharmacokinetic model used in the simulation scenarios describing the systemic exposure to tramadol during titration and maintenance phases of treatment in paediatric chronic pain patients.

Clinical Trial Simulations -Dose Rationale for Titration and Maintenance Phases
In addition to the identification and selection of suitable doses for up titration and maintenance phases of the protocol, attention was given to the optimization of blood sampling and assessment of gabapentin exposure in children.First model performance was assessed by comparing the anticipated profiles obtained with limited sampling (Figure S5).To ensure the proposed sampling scheme yields successful estimation of the parameters of interest, a simulation-estimation procedure was implemented using random sampling based on the recommended sampling intervals, with four samples per patient (n=94).Primary and secondary individual pharmacokinetic parameters were then derived using $PRIOR in NONMEM, with informative priors on all parameters.

Tramadol Dosing Interval
To ensure the trial remains fully blinded, tramadol should be given three times a day to replicate gabapentin's dosing interval.Therefore, simulations were undertaken to assess the safety of shifting the dose from its recommended q.i.d. to a t.i.d.regimen using the maximal unit dose of tramadol for each scenario.
As shown in Figure S6, concentration vs. time profiles after an increase of 32% in tramadol amount per dose unit results in a proportional increase in peak concentrations and overall systemic exposure.This increase was deemed to be acceptable and clinically safe.

Figure S1.
Figure S1.Gabapentin exposure-response relationship derived from dose ranging studies in adult neuropathic pain patients using the Likert pain scale (Neurontin®, NDA submission file[1] ).
Residual variability was described by combined additive and proportional errors.Covariates included in the model by Ouellet et al. were creatinine clearance and race on oral clearance, and body weight and population (epileptic patients or healthy subjects) on volume of distribution.

Figure S2 .
Figure S2.Diagram of the final population PK model describing the disposition of gabapentin.CL = clearance; Vd = central volume of distribution; Ka = first order absorption rate constant; Tlag = absorption lag time.Covariates include creatinine clearance on oral clearance (CL), and body weight on volume of distribution (Vd).
model with one compartment for the metabolite (M1), shown in Figure S3.Keeping in mind the correlation between clearance and weight, the proposed adaptation improved model performance, reducing inter-individual variability and residual error when compared with the original model.The final model parameters included clearance (CLe), apparent formation clearance of M1 (CLf), volume of distribution (V), transfer rate constants (K12, K21), absorption rate constant (Ka) and bioavailability (F).

Figure S3 .
Figure S3.Diagram of the final population PK model describing the pharmacokinetics of tramadol.Ka = first order absorption rate constant; Clf = apparent formation clearance of the metabolite M1; Cle = clearance of tramadol; ClM1; clearance of the metabolite; K12 & K21 = transfer rate constants.

Abbreviations:
Abbreviations: V = Central volume of distribution; WT = body weight; Clf = Apparent formation clearance of the metabolite, M1; Cle = Clearance of tramadol; K12 & K21 = transfer rate constants; Ka = First order absorption rate constant; F = Oral bioavailability; θ = PK parameter estimation; ƞ = inter-individual variability; Ω = inter-individual or inter-occasion variability in population PK parameter; σ = population variance.Parameter estimates are listed together with their 95%-confidence intervals in parentheses.

Figure S4 .
Figure S4.Steps required for the creation of a virtual patient cohort including predefined demographic and clinical baseline characteristics.SCRE; serum creatinine values.

Figure S5 .
Figure S5.Simulated concentration vs. time profiles of gabapentin according to the proposed trial regimen.Panels depict profiles stratified by weight band.Solid line shows the median, shaded area indicates the 95% confidence interval.Black dots are random sampling points from simulated profiles (n=94) with re-estimated PK parameters using informative priors.

Figure S6 .
Figure S6.Plot comparing a single dose of tramadol at its recommended maximum single dose to the proposed maximal dose for t.i.d.dosing regimen.The t.i.d.regimen was required to ensure blinding of the treatment in the GABA-1 trial.Predicted concentration is shown as the median (soli red line) and 95% confidence interval (red shaded area) along with the 5 th and 95 th percentiles and the corresponding 95% confidence interval (black lines and blue shaded areas).

Table S2 .
Parameter estimates of the final pharmacokinetic model used in the simulation scenarios describing the systemic exposure to gabapentin during titration and maintenance phases of treatment in paediatric chronic pain patients.Cl = clearance; Vd = central volume of distribution; Ka = first order absorption rate constant; Tlag = absorption lag time.Parameter estimates are summarized together with their 95 % confidence intervals.